Erythropoietin (EPO) is a glycoprotein hormone which is involved in the maturation and differentiation from erythroid progenitor cells to mature erythrocytes, and is a monomeric polypeptide composed of 165 naturally occurring amino acids (Non-Patent Document 1).
Human EPO is essential in the proliferation and differentiation of erythrocytes, and is useful for the treatment of blood diseases characterized by decreased production of erythrocytes. From a clinical aspect, EPO is used in the treatment of anemia in chronic renal failure (CRF) patients, autologous blood donation, and anemia of prematurity (Non-Patent Documents 2 to 4), as well as for AIDS patients and cancer patients under chemotherapy (Non-Patent Document 5). Furthermore, EPO has been proved to be effective in chronic anemia.
EPO is produced mainly in the kidney in adults, but is also produced in the astrocytes and neurons of the central nervous system, so that EPO and EPO receptors are expressed in the capillary blood vessels at the encephalo-peripheral boundaries. It has been reported that when EPO is systemically administered, EPO passes through the blood-brain barrier and reduces the loss of neuronal cells responding to cerebral and spinal cordischemia, mechanical trauma, epilepsy, excitotoxin, and neuroinflammation (Non-Patent Documents 6 to 10).
In the therapy using proteins such as EPO, there are problems such as short plasma half-life due to the susceptibility to degradation by proteases (Non-Patent Documents 11 and 12), and the necessity of multiple intravenous injections in order to maintain the therapeutically effective concentration of the compounds in the circulatory system. Furthermore, subcutaneous injection may replace intravenous injection as a route of administration, and this subcutaneous injection has a slow release effect because absorption from the site of administration is slow. However, the plasma concentration in this case is significantly lower than that obtainable by intravenous injection. Thus, the same number of injections as in the case of intravenous injection must be given in order to obtain an equivalent therapeutic effect, so that this poses a burden to patients. Also, since human serum EPO is a glycoprotein, and since the structures of the sugar chains bonded to the EPO surface are complicated, with a wide and diverse range of glycosylation products being available, human serum EPO molecules exhibit non-uniformity in size. Thus, there is also a problem that human serum EPO cannot be produced with good reproducibility using recombinant human EPO.
Therefore, there is a need for a method and a compound for increasing, not an EPO having low bioavailability in the treatment of diseases attributable to decreased production of EPO, including anemia as described above, but for increasing an endogenous EPO, in the relevant technical field.
On the other hand, it is known that the amount of production of EPO is regulated by the oxygen concentration through intervention of the hypoxia inducible factor (HIF), which is a transcription factor (Non-Patent Document 13). That is, in normoxia, an HIF subunit (HIF-1α) in which a proline residue has been hydroxylated by 2-oxoglutarate dioxygenase enzyme, is decomposed by the ubiquitin-proteasome system, and thus production of EPO is not enhanced. However, in hypoxia, hydroxylation of the proline residue of HIF-1α by 2 oxoglutarate dioxygenase enzyme is suppressed, and as a result, stabilized HIF-1α migrates from the cytoplasm into the nucleus and forms a dimer with HIF-1β. This dimer is bonded to the hypoxia responsible element (HRE) sequence of EPO gene and enhances transcription, and thereby enhances the production of EPO.
Enzyme inhibitors against HIF prolyl hydroxylases such as 2-oxoglutarate dioxygenase enzyme, which utilize such an EPO production mechanism, have been reported as EPO production enhancers (Patent Documents 1 to 4).
However, genes that expressions are regulated by HIF include not only those genes encoding EPO, but also genes encoding the vascular endothelial growth factor (VEGF), and the like. It has been reported that VEGF has angiogenesis promoting activity, and thus may cause exacerbation of malignant tumors through this angiogenesis enhancing function (Non-Patent Documents 14 and 15). Furthermore, anemia is also caused by chemical treatments targeting cancer, and thus, administration of a therapeutic drug for anemia to cancer patients under such chemotherapy may also be contemplated (Non-Patent Document 5). Therefore, a compound having a HIF prolyl hydroxylase enzyme inhibitory activity, which also has a possibility of enhancing the expression of VEGF and the like capable of exacerbating cancer, involves the risk of exacerbating cancer as well.
The production of EPO is regulated by a promoter which is located on the 5′-terminal side of EPO and an enhancer which is located on the 3′-terminal side, and it is contemplated that HIF binds to the HRE sequence in the enhancer, and thereby enhances the production of EPO. In addition, GATA-2, NFκB and the like are also believed to regulate the production of EPO (Non-Patent Documents 16 and 17), and it is thought that enhancing the production of EPO can be achieved as well by mechanisms other than the HIF prolyl hydroxylase enzyme active inhibition. Under such circumstances, it is thought that a compound having an EPO production enhancing activity that is not dependent on the HIF prolyl hydroxylase enzyme active inhibition is useful for the treatment of anemia.
Furthermore, EPO enhances the proliferation and maturation of erythroid progenitor cells as described above, but compounds having an activity of enhancing the maturation and differentiation of erythroid progenitor cells without the intervention of EPO production, are also useful as therapeutic agents for anemia. Compounds having an activity of enhancing the blood cell proliferation enhancing activity EPO possesses or compounds having an inhibitory activity against hematopoietic cell phosphatase that catalyzes dephosphorylation, which is one of important regulatory mechanisms in the signal transduction of EPO, have been reported (Patent Documents 5 to 7); however, it cannot be said that their activities are undoubtedly satisfactory. Furthermore, reports have been made on synthetic peptides and hematides that have effect on EPO receptors (Non-Patent Document 18); however, there is a problem that in order to make the peptides and hematides to show an activity equivalent to that of EPO, high dosage administration is required, and the peptides and hematides cannot be orally administered. A low molecular weight compound having a 2-phenylquinoline skeleton has also been reported (Patent Document 17).
Therefore, an orally administrable, low molecular weight therapeutic agent for anemia which has both an EPO production enhancing activity and a hemoglobin production enhancing activity is considered to be useful for the treatment of anemia in the future.
On the other hand, there have been disclosed compounds having the tetrahydroquinoline skeleton according to the present invention, which are used as a CRTH2 inhibitor that is effective for inflammatory diseases (Patent Documents 8 to 11), an eosinophil infiltration suppressant that is effective for inflammatory diseases (Patent Document 12), an upregulator of ecdysone steroid hormone receptor expression that is involved in the growth, ecdisys and development of insects (Patent Document 13), a β-amyloid precursor protein secretion enhancer that is effective for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (Patent Document 14), a STAT6 activation suppressant that is effective for atopic dermatitis and the like (Patent Document 15), and apolipoprotein A-I production enhancer that is effective for hyperlipidemia (Patent Document 16). However, there is no description or suggestion that these compounds have an EPO production enhancing activity or a hemoglobin production enhancing activity, and a compound having a tetrahydroquinoline skeleton which is useful as a prophylactic and/or therapeutic agent for anemia is not known at all.